Blocking RhoA/ROCK inhibits the pathogenesis of pemphigus vulgaris by suppressing oxidative stress and apoptosis through TAK1/NOD2-mediated NF-κB pathway

Abstract

Oxidative stress and apoptosis play critical roles in pemphigus vulgaris (PV). The main aim of the present study was to investigate the effects of RhoA/ROCK signaling on UVB-induced oxidative damage, and to delineate the molecular mechanisms involved in the UVB-mediated inflammatory and apoptotic response. In HaCaT cells, we observed that blockage of RhoA/ROCK signaling with the inhibitor CT04 or Y27632 greatly inhibited the UVB-mediated increase in intracellular reactive oxygen species (ROS). Additionally, inhibition of RhoA/ROCK signaling reduced UVB-induced apoptosis, as exemplified by a reduction in DNA fragmentation, and also elevated anti-apoptotic Bcl-2 protein, concomitant with reduced levels of pro-apoptotic protein Bax, caspase-3 cleavage and decreased PARP-1 protein. The release of inflammatory mediators TNF-α, IL-1β, and IL-6 was also attenuated. Mechanically, we observed that blockage of RhoA/ROCK repressed the TAK1/NOD2-mediated NF-κB pathway in HaCaT cells exposed to UVB. Taken together, these data reveal that RhoA/ROCK signaling is one of the regulators contributing to oxidative damage and apoptosis in human keratinocytes, suggesting that RhoA/ROCK signaling has strong potential to be used as a useful therapeutic target in skin diseases including PV.

Escherichia coli Nissle 1917 Protects Intestinal Barrier Function by Inhibiting NF-κB-Mediated Activation of the MLCK-P-MLC Signaling Pathway

“…Despite advanced development in the research of sepsis, the mortality rate among sepsis patients remains high. Because sepsis is a heterogeneous disease, people with sepsis always experience multiple organ dysfunction, including the lung, central nervous system, cardiovascular system, liver, kidney, and intestinal injury [2]. The gut, which consists of epithelial cells, immune systems, and microbiota, was assumed to be the promotor of this critical disease.…”

Vasodilator-Stimulated Phosphoprotein: Regulators of Adipokines Resistin and Phenotype Conversion of Epicardial Adipocytes

“…Furthermore, there is increasing evidence that the RhoA signaling pathway plays a critical role in the inflammatory response [ 17 ]. In our study, blockade of ROCK activity by Y-27632 inhibited production of proinflammatory cytokines such as IL-6, IL-8, MCP-1, and TNF-α ( Figure 6 ), which is consistent with previous studies.…”

Association of NFKB1 ‐94ATTG ins/del polymorphism (rs28362491) with pemphigus vulgaris

“…The altered function of IRAK1/NF‐kB pathway, which could be the result of gene polymorphisms, may predispose to the susceptibility of pemphigus if we take into account the reported increase of several inflammatory cytokines and chemokines in skin inflammation conditions . On the other hand, the blocking of NF‐κB–mediated pathways by the appropriate pharmacological treatment was reported as a way of inhibiting the PV pathogenesis . The present study focused on the association of three genetic variants that concern the IRAK1/NF‐kB pathway and specifically the genes IRAK1, NFKB1 and NFKBIA.…”

“…PV is an immune blistering disease, but little is known about the role of these genes and related polymorphism in PV susceptibility . Up to date, only the attenuation of pro‐inflammatory cytokines by blocking NF‐κB–mediated pathways was documented, which inhibited the pathogenesis of PV by suppressing oxidative stress and apoptosis in human keratinocytes . The aim of the present study was to explore the role of polymorphisms in IRAK1/NF‐κB signalling pathway in PV predisposition.…”